Mechanisms of inflammasome activation and pyroptosis induction by HIV

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The progressive loss of CD4 T cells during HIV progression in non-treated patients leads to the clinical syndrome AIDS. Activated CD4 T cells die through caspase-3 mediated apoptosis during HIV infection. However, the large majority of CD4 T cells (more than 95%) that die during HIV infection are quiescent lymphoid CD4 T cells. Recently, it has been discovered that these quiescent lymphoid CD4 T cells undergo caspase-1 mediated pyroptotic cell death rather than apoptosis after HIV infection. It is thought that aberrant nucleic acids are produced during the process of so-called abortive infection which are directly recognized by the nuclear nucleic acid sensor IFI16. IFI16, in turn, forms an active inflammasome together with the adapter protein ASC in a paranuclear area leading to auto-proteolytic activation of caspase-1. Active caspase-1 proteolytically activates members of the IL-1b cytokine family and mediates pyroptosis. Of note, peripheral quiescent CD4 T cells do not die from IFI16-mediated pyroptosis upon HIV infection, unless they receive signals from lymphoid quiescent CD4 T cells. The mechanisms underlying the cell type and activation dependent induction of the IFI16 inflammasome and subsequent pyroptotic cell death remain ill defined. We have performed extensive chemical biology screens in macrophages to better understand the mechanisms of inflammasome activation by other triggers. Our preliminary data show that many specific signaling pathways act to control inflammasome activation and influence the threshold of inflammasome responses to various triggers. In this proposal we aim to extend these studies and perform chemical biology screens in human lymphoid aggregate cultures (HLAC) infected with HIV to gain a better understanding of the mechanisms driving IFI16 inflammasome formation and pyroptosis induction. Through an integrated collaborative research plan we aim to identify and verify novel factors acting in HIV restriction in quiescent CD4 lymphoid CD4 T cells. We also aim to verify whether these newly uncovered pathways more generally regulate the formation of other inflammasomes and pyroptosis in other cell types.